The serum level of vitamin D and prevalence of vitamin D deficiency among children with asthma in Asia and Africa: a systematic review and meta-analysis

Background Several studies on the serum level of vitamin D and the percentage of vitamin D deficiency in children with asthma have been conducted in Asia and Africa, but the results have been inconsistent and inconclusive, requiring a systematic review and meta-analysis to assess the strength of the evidence. Objective The objective of this review is to synthesize evidence on serum levels of vitamin D and the percentage of vitamin D deficiency among children with asthma in Asia and Africa. Methods To identify relevant articles, a comprehensive search was conducted across various databases and repositories such as PubMed, Google Scholar, Hinary, Web of Science, ResearchGate, as well as gray literature sources. The Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines were followed during the retrieval process. Data extraction was performed following a standardized format based on the JBI (Joanna Briggs Institute) data extraction guidelines. Microsoft Excel was utilized for data extraction, and subsequently, the data was exported to STATA 17 for further analysis. To assess the heterogeneity among the included studies, Cochrane Q-statistics and the I2 tests were employed. Publication bias was assessed using the Egger test and funnel plot. Result This meta-analysis investigated 33 articles encompassing a total of 3432 children diagnosed with asthma. The findings demonstrated that in low- or middle-income countries across Africa and Asia, children with asthma had an average serum vitamin D level of 21.9 ng/ml (95% confidence interval [CI]: 18.0–25.9 ng/ml), with 53.7% (95% CI: 40.5–66.9) experiencing vitamin D deficiency. Additionally, when considering the continent, children with asthma in Asia had an average serum vitamin D level of 18.5 ng/ml (95% CI: 13.8–23.3), while those in Africa had a level of 28.7 ng/ml (95% CI: 22.7–34.8). The analysis further explored different sub-group analyses. Depending on the study design, case–control studies yielded an average serum vitamin D level of 20.3 ng/ml (95% CI: 18.2–22.4), whereas cross-sectional studies resulted in 23.8 ng/ml (95% CI: 17.5–30.1). Based on publication year, studies published on or before 2015 had an average serum level of 21.0 ng/ml (95% CI: 18.0–24.0), while those published after 2015 had a level of 22.4 ng/ml (95% CI: 17.2–27.7). Moreover, when considering sample size, studies with 100 participants or less had an average serum level of 21.7 ng/ml (95% CI: 17.3–26.1), while studies with more than 100 participants had a level of 22.1 ng/ml (95% CI: 18.6–25.6). Conclusion Children with asthma in Asia and Africa were found to have low serum levels of vitamin D and a high percentage of vitamin D deficiency. This highlights the importance of early detection and monitoring of vitamin D levels in these children to prevent potential complications associated with vitamin D deficiency. Taking proactive measures to address and manage vitamin D deficiency is crucial for the well-being of children with asthma in these regions.


Introduction
Asthma, a prevalent chronic lung disease in children and adults [1,2], causes symptoms like coughing, wheezing, and breathing difficulties due to narrowed airways [1,3].The risk factors for asthma include having a family history, respiratory infections, exposure to air pollution, smoking, allergies, and weather condition [1,3,4].Children with asthma commonly experience sleep problems, recurrent respiratory infections, fatigue, learning disabilities, and growth retardation [2,5,6].If left untreated or poorly managed, childhood asthma can lead to complications such as obstructive sleep apnea, anxiety, pneumonia, and even respiratory failure [6][7][8].
Asthma is a significant global health issue, with a considerable number of deaths and a high prevalence of affected individuals.In 2019, asthma was responsible for 455,000 deaths, impacting an estimated 262 million people [1].Particularly in Africa, there has been a substantial increase in the number of children with asthma between 1990 and 2010, there were 34.1 million and 49.7 million more children with asthma in Africa [9], and asthma is also becoming more prevalent in Asia [10].
Vitamin D has been increasingly associated with the development and management of asthma.It plays a role in activating specific immune cells that regulate the severity and frequency of asthma attacks [11][12][13].Additionally, higher vitamin D levels have been linked to reduced inflammation markers and improved control of asthma symptoms [12,14,15].However, many children with asthma have low levels of vitamin D, which may lead to more frequent asthma attacks and increased reliance on medications [14,16].The normal vitamin D level for children is considered to be equal to or greater than 50 nmol/L [17], but most children with asthma have been found to have levels below 20 ng/ml [14,18,19].These levels are categorized as insufficient (20 to 30 ng/ml) or deficient (< 20 ng/ml) according to reference laboratories [20,21].
Asthma and vitamin D deficiency often coexist and can have a reciprocal negative impact on each other [12,16].Children with asthma are more likely to have vitamin D insufficiency or deficiency, which is associated with increased asthma symptoms, exacerbations, decreased lung function, higher medication use, and more severe disease [22,23].The prevalence of vitamin D deficiency in children with asthma varies widely, ranging from 28.5% to 90.6% [24,25], with mean values ranging from 9.0 ng/ml to 68.6 ng/ml [26,27].
While several studies have explored the relationship between vitamin D levels and asthma in children from Africa and Asia, the findings have been inconsistent and inconclusive.Hence, the scope of this study is to conduct a systematic review and meta-analysis focused on examining the serum levels of vitamin D and the percentage of vitamin D deficiency among children with asthma specifically in the Asian and African continents.The study aims to synthesize and analyze existing evidence from relevant studies conducted in these regions to provide a comprehensive understanding of the relationship between vitamin D status and asthma in children.Additionally, the study seeks to explore potential variations across different populations and evaluate the impact of vitamin D levels on asthma outcomes among children in Asia and Africa.

Review question
This systematic review and meta-analysis aimed to answer two main questions: What are the vitamin D serum levels among children with asthma in Africa and Asia? and what is the prevalence of vitamin D deficiency among children with asthma in Africa and Asia?

Reporting
The review protocol has been sent to the PROSPERO database for registration with ID 422317.The systematic review and meta-analysis were reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [28] statement guideline to determine the serum level of vitamin D and percentage of vitamin D deficiency among children with asthma in African.A systematic search was conducted across various international databases, such as PubMed, Google Scholar, Hinary, Web of Science, ResearchGate, as well as gray literature sources (Table 1).

Eligibility criteria Inclusion criteria
Study area Studies conducted on the Asia and African.
Publication conditions Articles published in peerreviewed journals and articles available on the university website.
Study design All observational study designs (crosssectional and case-control) reporting the serum level of vitamin D and/or percentage of vitamin D deficiency among children with asthma in Asia and Africa countries were considered.
Outcome of interests Studies reported data on the serum level of vitamin D and percentage of vitamin D deficiency among children with asthma in Asia and/ or Africa were considered in the Population, Exposure, Comparison, and Outcome (PICO) format.
Language Articles reported in the English language were considered.

Exclusion criteria
Articles, which were not fully accessed, were excluded because of inability to assess the quality of articles in the absence of full text and to estimate the outcome variable.Moreover, case reports, case series, and studies not differentiating asthma children from other respiratory disorders were excluded from the study.

Outcome measurement among children with asthma
This systematic review has two main outcome variables.The primary outcome variable of this study is a percentage of vitamin D deficiency.The percentage of vitamin D deficiency was calculated from each primary study by dividing the number of vitamin D deficiency with asthma by the total number of children with asthma multiplied by 100 [29,30].The second outcome was to determine the serum level of vitamin D [30,31].According to the criteria established in this study, children are defined as individuals who are younger than 18 years of age.

Data extraction
All titles and abstracts were exhaustively screened through using a standardized JBI data extraction format to extract all potentially relevant data.The primary author, continent/country, year publication, study area, study design, sample size, and serum level of vitamin D with 95% confidence intervals or with the standard deviation score of each study were included in the data extraction format.Further information and differences of opinion were settled by discussion and agreement at the time of data abstraction.
The retrieved studies were exported to the citation manager (Zotero) and then duplicate articles were excluded.Disagreements were discussed during a consensus meeting with other reviewers for the final selection of studies to be included in the systematic review and meta-analysis.

Quality assessment
The Joanna Briggs Institute Critical Appraisal tool for use in JBI Systematic Reviews (JBI-MAStARI) was used to assess the trustworthiness, relevance, and results of published papers [32].The tool compromises eight main standards for evaluating each primary study critically.As a result, primary studies that had a score of 50% or higher were included in the systematic review and meta-analysis study.

Statistical analysis
The extracted data were edited, cleaned, and checked for completeness in a Microsoft Excel sheet, and then exported into STATA 17 for further analysis.Pooled overall serum level of vitamin D and percentage of vitamin D deficiency among children with asthma were estimated through a random effect meta-analysis model.Cochrane Q-statistics and the I2 test's p-values were used to assess the heterogeneity of reported serum levels of vitamin D and the percentage of vitamin D deficiency among studies [33,34].
The publication bias was estimated through the Egger test and funnel plots [35] and sensitivity analysis was piloted to examine the effect of a single study on the overall estimation.Moreover, subgroup analysis was performed by the study continent, study design, sample size, and year of publication.

Results
Out of the initial pool of 1750 studies, after removing duplicates, 577 studies remained.Among these, 434 studies were excluded based on the assessment of their titles, abstracts, and study nature (such as case reports and qualitative studies).After this exclusion, 143 fulltext articles were assessed, and 110 of them were further excluded as they did not report the outcome variable of interest.finally, a total of 33 studies with full-text articles were included in the review.These studies involved a combined sample size of 3,432 participants.The studies were conducted in 12 different countries across Africa and Asia, including Egypt, Turkey, Nigeria, Iran, China, India, South Korea, Tunisia, Israel, Iraq, Thailand, and Qatar.(Fig. S1).

Characteristics of the included articles
A total of 3,432 asthmatic children from 12 countries in Asia and Africa were included in the 33 studies comprising this meta-analysis, published between 2011 and 2022.
All of the studies included in this review were observational stuies, with a sample size ranging from 36 participants reported from a study in Egypt [64], and 483 from Qatar [63].
Of the 33 studies, 27 studies described both the serum level of vitamin D and the percentage of vitamin D deficiency, whereas, 6 studies only reported the serum level of vitamin D in children with asthma in Africa and Asia continents (Table 2).

Meta-analysis
The pooled estimation of serum levels of vitamin D and the percentage of vitamin D deficiency among children with asthma in Asia and Africa was derived based on the following studies: Thirty-three studies (n = 33) provided data on serum levels of vitamin D, and twenty-seven (n = 27) studies reported the percentage of vitamin D deficiency.The serum level of vitamin D ranged from the highest reported level in Nigeria, 68.6 ± 25.9 ng/ml [27], to the lowest reported level in Iraq, 2.05 ± 0.4 ng/ml [61].
Moreover, the percentage of vitamin D deficiency ranged from the highest reported from a study in Turkey 82.2% [45], to the lowest report was from Nigeria 1.5% [27].
The pooled serum level of vitamin D among children with asthma in Africa and Asia was found to be 21.9 ng/ ml (95%CI; 18.0-25.9ng/ml), as displayed in (Fig. S2).
Moreover, the percentage of vitamin D deficiency children with asthma in Africa and Asia was found to be 53.7%(95%CI; 40.5-66.9)(Table 3).

Sub group analysis of pooled of serum levels of vitamin D among children with asthma in Africa and Asia
The subgroup analysis was employed for a dual purpose, as it not only estimates the pooled mean within each group but also tests for differences in the pooled means between groups for deeper into the subject matter to ensure a comprehensive understanding.

Sub group analysis of pooled percentage of vitamin D among children with asthma in Asia and Africa
The subgroup analysis was employed to estimate percentage of vitamin D by stratifying the studies into different categories.In this regard, the studies were stratified by continent, study design, year of publication, and sample size.The pooled percentage of vitamin D among children with asthma by continent in Asia and Africa was found to be 57.1%(95%CI;44.1-70.1)and 47.8%(95%CI;  4) respectively.

Publication bias
Egger's test was used to explain the visual for detecting bias or systematic heterogeneity of serum level of vitamin D and percentage of vitamin D among children with asthma in Asian and African (Table 5).Moreover, the funnel plot also determines the publication bias of serum level of vitamin D and percentage of vitamin D among children with asthma in Asian and African (Fig. S7-8).Furthermore, the results of sensitivity analyses were also examined of serum level of vitamin D and percentage of vitamin D among children with asthma in Asia and Africa respectively (Table 6 and Fig. S9).

Discussion
This study aims to estimate the pooled serum level of vitamin D and the percentage of vitamin D deficiency among children with asthma in the Asian and African.
In this regard, the pooled serum level of vitamin D and the percentage of vitamin D deficiency was found to be 21.9 ng/ml (95%CI; 18.0-25.9ng/ml), and 53.7% (95%CI; 40.5-66.9)among children residing in low-or middleincome countries in Africa and Asia respectively.
The serum level of vitamin D among children with asthma in this review was consistent or lower than the study conducted in Russia [65], Mexico [66], UK [67], Italy [68], and U.S.A [69].Moreover, the proportion of vitamin Deficiency in this study is higher than the study conducted in Spain [70], in U.S.A [69], and in Mexico [66].
This difference might be this review was conducted in a resource-limited setting whereas the above studies were conducted in developed countries since in developed countries the health care provider, patients, and stakeholders may have good equipment, knowledge, and quality of care to reduce and prevent the deficiency of vitamin D among children with asthma.Moreover, supplementation of vitamin D and early detection might be higher in developed countries as compared with a resource-limited setting [71][72][73].
However, the percentage of vitamin D deficiency among children with asthma in this study is lower than  several other studies conducted in Brazil [74], Russia [65], and UK [23].This discrepancy might be the cut value difference in defining vitamin D deficiency, For example, the cut of vitamin D deficiency in the study conducted in the UK was < 50 nmol/l whereas in this study was < 20 nmol/l [23].Moreover, the study participant difference or the level of severity/attack or recurrent wheezing might be contributing to this difference [74].
The findings in this review will fill an evidence gap on the average mean value of vitamin D and the extent of vitamin D deficiency among children with asthma in resource-limited settings (i.e.Asia and Africa).Moreover, the review findings illuminate the high prevalence of vitamin D deficiency among children with asthma, offering valuable insights to stakeholders, including non-governmental and governmental organizations, and researchers in the field of childhood asthma.These insights can help focus attention and efforts on mitigating the burden associated with this issue.Given the frequent co-occurrence of asthma and vitamin D deficiency, it is important to address both conditions as they exacerbate each other.[12,16].The majority of asthmatic infants have low vitamin D levels, which could make asthma attacks frequent, and severe, and increase the demand for drugs [14,16].
This study is the estimate the pooled serum level of vitamin D and the percentage of vitamin D deficiency among children with asthma to recognize the issue in general.In addition to that, the study also perform a sub group analysis to see the serum level of vitamin D and the percentage of vitamin D deficiency between the group, it allows researchers to test their hypotheses in more detail, and It is important to understand the risks associated with this kind of analysis of serum level of vitamin D associated with childhood asthma [75][76][77].Given the significance of a large sample size for accuracy, the reported pooled serum level of vitamin D and the percentage of vitamin D deficiency among children with asthma in Asia and Africa may potentially be underestimated in this study.Moreover, recent studies focusing on this specific population in the region have indicated a decline in vitamin D levels and an increase in the prevalence of vitamin D deficiency among children with asthma.To avoid drawing misleading conclusions influenced by confounding factors, it is crucial to take into account the subgroup analysis findings presented in this study.These findings highlight the variability in serum vitamin D levels and deficiency rates across different subgroups based on factors such as continent, study design, year of publication,  and sample size.Considering these factors will contribute to a more accurate understanding of the actual situation.

Limitations of the study
While this systematic review and meta-analysis approach multiple studies to estimate the prevalence of vitamin D deficiency and its impact on asthma outcomes in children from Asia and Africa, it is important to acknowledge a limitation.This review did not specifically assess the factors influencing serum levels of vitamin D and the percentage of vitamin D deficiency among children with asthma.Consequently, further research is needed to investigate these factors and gain a more comprehensive understanding of their role in the relationship between vitamin D status and asthma outcomes in this population.

Conclusion
The serum level of vitamin D was found to be low, and the percentage of vitamin D deficiency was found to be high among children with asthma in Asia and Africa.Hence, early detection level of vitamin D and its deficiency is crucial to prevent the complications associated with vitamin D deficiency among children with asthma to decrease the frequency, attack, and exacerbation of asthma in Africa and Asia because together worsen one another.

Table 1
The Search strategy of the serum level of vitamin D and the percentage of vitamin D deficiency among children with asthma in Asia and Africa

Table 2
The serum level of vitamin D and percentage of vitamin D deficiency distribution among children with asthma in Asia and Africa

Table 4
Summary of subgroup of vitamin D deficiency percentage among children with asthma by continent, study design, year of publication, and sample size in Asia and Africa

Table 5
Egger's test of serum level of vitamin D among children with asthma in Asia and AfricaTest of H0: no small-study effects P = 0.000 Number studies = 33, Root MSE = 21.45

Table 6
The sensitivity test of serum level of vitamin D among children with asthma in Asia and Africa